Despite recent advances in cancer treatment, the identification of novel anti-cancer therapeutic agents remains a pressing need. Heat Shock Protein 90 (Hsp90) is a molecular chaperone which binds to and folds several client proteins including a number of key cancer-relevant targets such as the kinases Bcr-Abl, Raf-1, and SRC family kinases such as SRC, LCK and FYN, mutated p53, ErbB2, and the steroid hormone receptors. Disruption of the folding process by Hsp90 inhibition leads to degradation of these client proteins. Because Hsp90 client proteins are so important in processes critical to the growth and survival of cancer cells (e.g., signal transduction and in transcription), Hsp90 inhibitors may serve as effective chemotherapeutic agents against a number of cancers. This hypothesis has been clinically validated by the geldanamycin analogs 17- AAG, and 17-DMAG. However, these ansamycin analogs suffer from poor pharmacokinetic properties and off- target toxicity. Thus, there is a need for improved Hsp90 inhibitors. This Phase I proposal focuses on synthesis, biological assessment and crystallography of four novel series of Hsp90 inhibitors that were designed using Locus' innovative computational technology. The ultimate proposed product of this research is an orally administered cancer therapeutic drug targeting Hsp90. [unreadable] [unreadable] [unreadable]